The anterior pituitary gland develops from a midline structure called Rathke~s pouch into five cell types, corticotropes, gonadotropes, thryrotropes, somatotropes and lactotropes. The gland integrates complex feedback mechanisms , receiving information from the brain via the hypothalamus, signaling to peripheral endocrine organs, and thereby regulating such vital processes as metabolism, growth, reproduction and behavior. The mechanisms of many diseases occurring in these processes can be revealed by characterizing factors that control pituitary development. The long-term objectives of the proposal is to identify signal molecules and corresponding transcriptional factors that control the pituitary organ commitment and cell lineage specification. The specific aims of the proposal are 1) to characterize signal pathways that control pituitary commitment and cell lineage determination by transgenic studies: experiments are proposed to disrupt BMP-4, Wnt-5A and FGF8 signaling pathways implicated in pituitary development by transgenic expression of dominant negative forms of BMP4 and FGF8 receptors and wildtype GSK3 that impairs Wnt signaling 2)to characterize a novel forkhead/HNF-3 factor implicated in mediating BMP-4 signaling in pituitary development by targeted gene disruption through homologous recombination; 3) to characterize a novel bHLH factor implicated in cell type specification in pituitary: a novel bHLH transcriptional factor that expresses between e10-e16 during pituitary development have been identified and will be characterized genetically by creating knock-out mice through homologous recombination.